The production of widely different and specialized cell types from a single omnipotent zygote involves large-scale transcriptional changes and chromatin recombination. Pioneer transcription factors play a key role in the programming of the epigenome and are capable to facilitate the recruitment of other regulatory factors in the standardization and differentiation steps of the continuous cell lineage. Research group of Prof. Liang Xingqun and Sun Yunfu published a research paper entitled as Pioneering function of Isl1 in the epigenetic control of cardiomyocyte fate on Cell Research online. The study revealed that the Isl1 / Brg1-Baf60c complex plays a crucial role in coordinating cardiac development and establishing epigenetic memory of the fate of cardiac myocytes.

Differentiation of stem or progenitor cells into different lineages concerns a series of large-scale transcriptional changes and chromatin recombination. Tissue-specific transcription factors and epigenetic modification factors work together to program the epigenome and establish cell unity, which is further maintained by the epigenetic regulatory mechanism. In order to initiate cellular programmed design, one special type of transcription factor, the pioneer transcription factor, inserts development-silenced genes into the "enclosed" chromatin covered by nucleus. Pioneer factor alone is not enough to activate genes, but it gives chromatin the ability to open transcription. Chromatin open is helpful to the following recruitment of additional transcription factors and other regulatory proteins, these proteins work together in the a series of steps of lineage explanation and heart occurrence process to induce the cell type specific gene program expression, and multiple transcription factors cooperate with each other and are integrated in the network of regulation, which strictly control the transcription program ensuring the normal development of the heart.

Isl 1 is a kind of LIM- homologous domain transcription factor that is transiently expressed in SHF progenitor cells prior to differentiation and integrating into cardiac tubes. These cells are added to the artery and vein poles of the cardiac tube to make it continue to grow and form the complicated morphogenesis model. The deployment and differentiation of SHF cardiac progenitor cells are the main reason of human congenital heart malformation in a very great degree, which highlights the importance of the more comprehensive understanding of the the mechanism of heart development mediated by SHF. Genetic studies in mice have shown that Isl 1 plays a key role in the development of SHF, which suggests that Isl 1-deficient mouse embryos lack all structures extracted from SHF, including right ventricle (RV), outflow tract (OFT) and most atria. Because Isl 1 is necessary for the proliferation, survival, migration and differentiation into different cardiac lines of SHF CPC. Recent studies found that Isl 1 variants and deletions are relevant to congenital heart disease. Although Isl 1 plays a key role in heart development and disease, detailed insights into its molecular patterns of action are severely deficient.

Here, the study shows that Isl1 serves as a precursor to the myocardial cell lineage through shaping the chromatin landscape of cardiac progenitor cells. In the Isl1 subtype mouse series showing congenital heart defects, Isl1 combined genome-wide analysis and RNA- and ATAC-sequencing of cardiac progenitor cells and their derivatives revealed the downstream regulatory network of Isl1, which coordinates cardiac initiation. The research of mechanism shows that Isl1 will combine with condensed chromatin and cooperate with the SWI/SNF complex based on Brg1-Baf60c so as to promote specific changes of heart lineage allowed in the chromatin landscape, which contain not only genes that have key function in cardiac progenitor cells but also highly expressed structure genes of myocardial cell when Isl1 itself no longer exists. Thus, the Isl1 / brg1-baf60c complex plays a crucial role in coordinating cardiac genesis and the epigenetic memory of establishing the fate of cardiac myocardial cells.

Professor Gergana Dobreva from Max Planck Institute of Cardiopulmonary Research, Prof. Sun Yunfu from TUSM and Prof.Sylvia M. Evans from University of California, San Diego, are co-corresponding authors of the paper. This research was supported by the National Natural Science Foundation of China.

Link：https://www.nature.com/articles/s41422-019-0168-1.pdf